Derivatives of 1,2,3,4-tetrahydroisoquinoline

ABSTRACT

This invention relates to new derivatives of 1,2,3,4tetrahydroisoquinoline having the general formula:   WHEREIN R1 and R2 are each a hydrogen atom or a lower alkyl radical, X is an oxygen or sulfur atom, and R3 is a phenyl radical having 1 to 3 substituent(s) selected from a group consisting of a lower, alkoxy, hydroxy, amino, nitro, halo(lower)alkyl radical and a halogen atom, production of the same and composition thereof. The compounds of this invention have relaxing activities on smooth muscles, especially on vascular-smooth and visceral smooth muscles.

United States Patent [191 Tanaka et a1.

1 1 Nov. 5, 1974 1 DERIVATIVES OF l,2,3,4-TETRAHYDROISOQUINOLINE [73]Assignee: Fujisawa Pharmaceutical Co., Ltd.,

Osaka, Japan 22 Filed: Dec. 20, 1971 21 Appl. No.: 210,213

[30] Foreign Application Priority Data Dec. 29, 1970 Japan 45-127198Dec. 29, 1970 Japan 45-127199 Dec. 29, 1970 Japan 45-127200 Dec. 29,1970 Japan 45-127202 Dec. 29, 1970 Japan 45-127201 [52] U.S. Cl. 260/283S, 260/155, 260/283 S, 260/287 R, 260/288 R, 260/287 R, 424/258 [51]Int. Cl C07d 35/10 [58] Field of Search 260/283 S, 289 R [56] ReferencesCited UNITED STATES PATENTS 2,663,709 12/1953 Craig 260/289 R 2,683,1466/1954 Robinson 260/289 R 3,042,671 7/1962 Lombardino 3,378,561 4/1968Montzka 3,389,141 6/1968 Montzka 260/289 R 3,437,662 4/1969 Gildersleeveet a1. 260/289 R 3,497,516 2/1970 Mashimo et a1. 260/289 R 2/1972Jcanmart 260/283 S 3/1972 Watanahe 260/289 R OTHER PUBLlCATlONS Rumpf et111., in Chem. Abstr., Vol. 66. C01. 7200Y (1967). Protiva et al., Chem.Abstr. Vol. 64, C01. 1755611 (1966) Abstracting Czech. 1 13,765.

Primary Examiner-Dona1d G. Daus Attorney, Agent, or Firm-Obl0n, Fisher,Spivak, McClelland & Maier [57] ABSTRACT This invention relates to newderivatives of 1,2,3,4- tetrahydroisoquinoline having the generalformula:

wherein R and R are each a hydrogen atom or a lower alkyl radical, X isan oxygen or sulfur atom, and R is a phenyl radical having 1 to 3substituent(s) selected from a group consisting of a lower, alkoxy,hydroxy, amino, nitro, halo(lower)alkyl radical and a halogen atom,production of the same and composition thereof. The compounds of thisinvention have relaxing activities on smooth muscles, especially onvascular-smooth and visceral smooth muscles.

39 Claims, No Drawings DERIVATIVES OF l,2,3,4-TETRAHYDROISOQUINOLINEThis invention relates to new derivatives of l,2,3,4tetrahydroisoquinoline having relaxing activities on smooth muscles.More particularly, this invention rewherein R, and R are eacha hydrogenatom or a lower alkyl radical, X is an oxygen or sulfur atom, and R is aphenyl radical having 1 to 3 substituent(s) selected from a groupconsisting of a lower alkoxy, hydroxy, amino, nitro, halo(lower)alkylradical and a halogen atom; to pharmaceutically acceptable saltsthereof; to methods for preparing the same; and to pharmaceuticalcompositions comprising these new derivatives or the salts thereof.

It is to be understood, within the scope of the present invention, thatthe term lower used in connection with an alkyl and alkoxy radicals isintended to mean an alkyl and alkoxy radicals having 1 to 6 carbon atomsunless otherwise indicated.

As a suitable lower alkyl radical in the above formula there may bementioned, for example, a lower alkyl radical having I to 6 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,pentyl or hexyl radical, and preferably a lower alkyl radical having 1to 4 carbon atoms, and more preferably a lower alkyl radical having 1 to2 carbon atoms.

As a suitable lower alkoxy radical in the above formula there may bementioned, for example, a lower alkoxy radical having 1 to 6 carbonatomssuch as methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy,t-butoxy, pentoxy, isopentoxy or hexyloxy radical, and preferably alower alkoxy radical having 1 to 4 carbon atoms, and more preferably alower alkoxy radical having I to 2 carbon atoms.

As a suitable halo(lowcr)alkyl radical in the above formula there may bementioned, for example, a halo(- lower)alkyl radical having I to 6carbon atoms such as chloromethyl, fluoroethyl, chloropropyl,bromopropyl, iodobutyl, chloropentyl, bromochloroethyl, dichloromethyl,dichloroethyl, difluoromethyl, dichloropropyl, trichloromethyl,tribromomethyl, trifluoromethyl, trichloroethyl or tribromoethylradical, and preferably a halo(lower)alkyl radical having 1 to 4 carbonatoms, and more preferably a halo(lower)alkyl radical having 1 to 2carbon atoms.

It is to be understood that the halogen atom in the above formulaincludes chlorine, bromine, fluorine and iodine atom.

The new derivatives of l,2,3,4- tetrahydroisoquinoline of the formula[I] and pharmaceutically acceptable salts thereof have relaxingactivities on smooth muscles, especially on vascular-smooth and visceralsmooth muscles. Accordingly, they show vasodilating,intestinal-contraction inhibiting and bladder-contraction inhibitingactivities, while not showing bronchodilating activities, and are usefulas vasodilat- 2 ing, intestinal-contraction inhibiting andbladdercontraction inhibiting agents.

According to the present invention, the new derivatives ofl,2,3,4-tetrahydroisoquinoline of the formula [I] can be prepared byvarious methods which are illustrated as follows:

The fundamental method is representable by the following reaction:

on R Hog l HO HO H0 (Ill 2 wherein R, and R are each a hydrogen atom-ora lower alkyl radical, X is an oxygen or sulfur atom, and R is a phenylradical having 1 to 3 substituent(s) selected from a group consisting ofa lower alkoxy, hydroxy, amino, nitro, halo(lower)a lkyl radical and ahalogen atom.

The reaction which is illustrated by the above reaction scheme iseffected by reacting the compound (II) or the salt thereof with thealdehyde compound (III), or with the acetal, hemiacetal or hydratethereof. Among the starting compounds (ll), 4-(2-aminoethyl)- catecholcan be prepared, for instance, bythe method reported in the ChemicalAbstracts, Volume 45 (1951), Column l97ld, and the other startingcompounds can also be prepared by methods similar to the said journalorother methods known in the art. The present reaction is preferablycarried out in the presence of an acid such as hydrochloric acid,sulfuric acid,

hydrobromic acid, acetic acid, propionic acid, picric acid or the like,with or without a solvent such as methanol, ethanol, benzene,chloroform, dioxane or other organic solvent inert to the reaction.There is no limitation to the reaction temperature. However, it ispreferably carried out with heating.

One-of the alternative methods is shown in the following scheme:

H0 1 HO *3.

OHZY CH2XR4 (v1 1 m (V) YCH CHO (VII) wherein Y is as defined above.

As a suitable acid residue of the compound (IV) there may be mentioned,for example, an acid residue of an acid such as hydrochloric acid,sulfuric acid, hydrobromic acid, hydroiodic acid, alkyl sulfuric acid,toluenesulfonic acid, dialkylcarbamic acid and the like.

The reaction which is illustrated by the above reaction scheme iseffected by reacting the compound (IV) or the salt thereof with thecompound (V), and it is preferably carried out in the presence of a basesuch as an alkali metal (e.g. sodium, potassium, etc.), alkali earthmetal (e.g. calcium, magnesium, etc.), alkali metal alkoxide (e.g.sodium methoxide, sodium ethoxide, potassium methoxide, potassiumethoxide, sodium propoxide, etc.), tertiary amine (e.g. pyridine,triethylamine, trimethylamine, dimethylaniline, etc.) and the like. Thepresent reaction is carried out with or without a solvent and preferablyin a solvent. As a suitable solvent there may be mentioned, forinstance, methanol, ethanol, ether, benzene, acetone, dioxane,acetonitrile, chloroform, monoor dichloroethane, tetrahydrofuran, ethylacetate, pyridine and other organic inert solvents in the reaction.There is no limitation to the reaction temperature.

Another alternative method is shown in the following scheme.

5 NH R60 CH2XR7 a (VIII) -IIX wherein R R an d X are each as definedabove, R and R are each a hydrogen atom, or individually or boundtogether protective groups of hydroxy radicals, and R is a phenylradical having I to 3 substituent(s) selected from a group consisting ofa lower alkoxy, nitro, hydroxy which may be protected with a protectivegroup, halo(lower)alkyl, amino radical and a halogen atom.

The starting compounds (VIII), which are novel ones, can be prepared byreacting a compound of the formula:

R OIU 2 F 2 R 0 q 1 wherein R R and R are each as defined above, with acompound of the formula:

R X CH COOH (XI) propoxycarbonyl, diphenylmethoxycarbonyl,2-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromomethoxycarbonyl, 3-iodopropoxycarbonyl2-furfuryloxycarbonyl, l-adamantyloxycarbonyl, 3-quinolyloxycarbonyl,trifluoroacetyl, benzyl, trityl, methoxymethyl, 2-nitrophenylthio, 2,4-dinitrophenylthio radical and the like.

As a suitable protective group of a hydroxy radical which R and R arebound together there may be mentioned, for example, an alkylene radicalsuch as methylene, dimethylmethylene, ethylene radical and the like.

The present reaction which is illustrated by the above reaction schemeis effected by reducing the compound (VIII) or the salt thereof. Thereducing reaction is conducted by a conventional manner known in thearts, for example, by a catalytic reduction, reduction with a reducingagent such as an alkaline metal aluminum hydride or alkaline metalborohydride, and reduction with an acid and metal. It is to beunderstood that the reducing method employed varies depending upon akind of the starting compounds (VIII), and that, if the hydroxy radicalsin the starting compounds (VIII) are protected with protective groups,it is necessary to conduct the reduction under a strong acidiccondition. In a catalytic reduction, the reaction is carried out in aconventional manner using a conventional catalyst such as palladiumcarbon, Raneynickel, platinic oxide and the like, and it may be alsocarried out under increasing pressure. When an alkaline metal aluminumhydride is used, the reaction is carried out a conventional manner in aconventional solvent such as diethyl ether, dibutyl ether,tetrahydrofuran, dioxane and the like. As a suitable alkaline metalaluminum hydride there may be mentioned, for example, an alkali metalaluminum hydride (e.g., lithium aluminum hydride, sodium aluminumhydride, etc.) and alkali earth metal aluminum hydride (e.g., calciumaluminum hydride, magnesium aluminum hydride, etc.). When anacid andmetal are used, the reaction is carried out a conventional manner usingan acid such as hydrochloric acid, sulfuric acid, acetic acid, etc. anda metal such as iron, zinc, tin, etc. When an alkaline metal borohydrideis used, the reaction is also carried out a conventional manner in asolvent as water, methanol, ethanol, tetrahydrofuran, dioxane, etc. As asuitable alkaline metal borohydride there may be mentioned, for example,an alkali metal borohydride (e.g., sodium borohydride, lithiumborohydride, etc.) and alkali earth metal borohydride (e.g., magnesiumborohydride, calcium borohydride, etc.).

If the symbol R in the above formula (VIII) is a phenyl radical havingnitro radical(s) as substituent(s), according to the present reactionwith nitro radical(s) will be connected into amino radical(s) with theexception when an alkaline metal borohydride is used as a reducingagent, and it is to be understood that the reduction accompanied withsuch side reaction also falls within the scope of the present invention.

A further alternative method is shown in the following scheme.

HO HO (iii) ing compounds can also be prepared according to a mannersimilar to the above method.

The present reaction which is illustrated by the above reaction schemeis effected by removing the protective groups of the compound (XII) orthe salt thereof. The reaction for removing the protective groups isconducted by a conventional manner known in the arts, for example, by ahydrolysis or catalytic reduction of the compound (XII) or the saltthereof. However, it is to be understood that the reaction condition forremoving the protective groups may vary depending upon the type of theprotective groups to be used. If the protective groups are, for example,radicals such as benzyl, benzyloxycarbonyl, substituted-alkoxycarbonyl,adamantyloxycarbonyl, trityl, methoxymethyl, sub- 0| dihydroxyl,2,3,4-tetrahydroisoquinoline stituted-phenylthio radical and the like,the protective groups may be removed by hydrolysis, which is carried outby treating the compound (XII) or the salt thereof with water preferablyin the presence of an acid such as hydrobromic acid, hydrochloric acid,formic acid,

acetic acid, trifluoroacetic acid and the like. The hyand the like. Ifthe protective groups are trifluoroacetyl radicals they can be easilyremoved only by treating the be understood that the other conventionalmethods for removing protective groups of hydroxy radicals may also beemployed.

It is to be further understood that the nitro radical(s) on the phenylring of the symbol R are connected into the amino radical(s) when acatalytic reduction is employed for removing protective groups ofhydroxy radicals, and that the present reaction for removing protectivegroups of hydroxy radicals accompanied with such side reaction alsofalls within the scope of this invention.

Typical compounds showing smooth muscle relaxing activities which fallwithin the category of the compounds of the formula [I] of thisinvention are illustrated in reference to some tests by which individualactive ingredients are the following numbered compounds.

Compound No. l

l-(p-Hydroxyphenoxy)methyl-6,7-dihydroxyl,2,3,4-tetrahydroisoquinolinehydrochloride Compound No. 2

l-(m-Hydroxyphenoxy)methyl-6,7-dihydroxyl,2,3,4-tetrahydroisoquinolinehydrochloride Compound No. 3

l-(o-Hydroxyphenoxy)methyl-6,7-dihydroxycompound (XII) or the saltthereof with water. It is to I 1,2,3,4-tetrahydroisoquinolinehydrochloride .Compound No.4

l-(3,4,5-Trimethoxyphenoxy)methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride Compound No. 5

l-(p-Methoxyphenoxy)methyl-6,7-dihydroxy- 1,2,3,4-tetraahydroisoquinoline hydrochloride Compound No. 6

l-(p-Chlorophenoxy)methyl-6,7-dihydroxyl ,2,3 ,4- tetrahydroisoquinolinehydrochloride Compound No. 7

1-(p-Fluorophenoxy)metheyl-6,7-dihydroxy- 1 ,2,3,4-tetrahydroisoquinoline hydrochloride Compound No. 8

l-(3,4-Dichlorophenoxy)methyl-6,7-dihydroxyl,2,3,4-tetrahydroisoquinolinehydrochloride Compound No. 9

l-( m-Trifluoromethylphenoxy )methyl-6 ,7

hydrochloride Compound No. 10

l-(2-Chloro-4-methoxyphenoxy)methyl-6,7- dihydroxy-l ,2,3,4-tetrahydroisoquinoline hydrochloride Compound No. 11

l-(p-Nitrophenoxy)methyl-6,7-dihydroxyl ,2,3 ,4- tetrahydroisoquinolinehydrochloride Compound No. 12

l-(p-Aminophenoxy)methyl-6,7-dihydroxy-l ,2,3,4-

' tetrahydroisoquinoline hydrochloride Compound No. 13

l-(m-Chlorophenoxy )methyl-6,7-dihydroxy-l ,2,3 ,4-tetrahydroisoquinoline hydrochloride Compound No. 14l-(p-I-lydrophenyl)thiomethyl-6,7-dihydroxy- Il,2,3,4-tetrahydroisoquinoline hydrochloride Compound No. 15

1(p-Methoxyphenyl )thiomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride Compound No. l6

l-(p-Chlorophenyl)thiomethyl-6,7-dihydroxyl,2,3,4-tetrahydroisoquinolinehydrochloride Compound No. 17

l-(o-Chlorophenyl)thiomethyl-6,7-dihydroxyl,2,3,4-tetrahydroisoquinoline hydrochlorideCompound No. 18

l-(p-Fluorophenyl)thiomethyl-6,7-dihydroxyl,2,3,4-tetrahydroisoquinolinehydrochloride Compound No. 19

1-(o-Fluorophenyl)thiomethyl-6,7-dihydroxy- '1,2,3,4-tetrahydroisoquinoline hydrochloride Test 1 Intestinal motilityin dogs:

Method: Mongrel dogs weighing 8 to 16 kg which were withheld from anyfood and water for 24 hours were anesthetized with a combination ofurethane (1.5 g/kg) and morphine (15 mg/kg). A balloon was placed at thejejunum of the dog, compressed at a pressure of l0/cm., and connected toa strain gauge. Changes in the motility were mainly recorded in terms ofamplitude, but taking account of the number of movements. The maximumchange of all the determinations, served as the calculation of the 50percent inhibition dose (ED The time required for percent recovery wasconsidered as the duration of action. Results are shown in the followingtable.

Compound No. i.v. (mg/kg) p.o. (g/ g) l 84 2.8 Compound No. ED Durationof action 5 4 21 21;

(min.) 6 I75 0.99

lb 139 I 2.8 1 8 l8 18 148 1.47 2 4.5 5 lsoprenaline 97 1.4 3 68 15 4 306 s 60 20 10 6 14 so This 1nvent1on'w1ll now be further descnbed byreferg ence to certain specific examples which are prov1ded 9 26 20herein for purposes of illustration only and are not inn tended aslimiting unless otherwise specified. 12 25 10 13 7.5 1s 14 29 12 15 2s10 Example 1. l6 4 15 17 3.2 15 A solut1on of 4-(2-am1noethyl)catecholhydrobro- :3 :8 mide (0.42 g) and 2-(p-methoxyphenoxy)-l ,1-

20 ethanediol (0.3 g) in dry benzene (20 cc) was refluxed for 4 hours.The solvent of the solution was distilled off Test 2- under reducedpressure, and the residue was recrystal- Blood flow of the internalcarotid and femoral arteries: f f a and t c l z Method: Mongrel dogsweighing 8 to 15 kg were co or 688 crys a S g o anesthetized withpentobarbital sodium (35 mg/kg). 2:2 5 352 figg mig t azg gi gfig '2 340 The left internal carotid artery and the right femoral q y arterywere mounted with probes of an electromagnetic flow meter, and the leftfemoral artery was connected to a stra1n gauge in order to measure thesystem1c blood Exam p16 2.

pressure. The heart rate was measured with a tachome- A solution of4-(2-aminoethyl)catechol hydrochloride (0.42 g) and2-(p-chlorophenoxy)acetaldehyde (0.35 g) in dry ethanol (20 cc) wasrefluxed for 4 hours. The solution was treated with an active carbon,and then the solvent was distilled off. The residue was treated withether to give crystals (0.65 g) ofl-(pchlorophenoxy)methyl-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinolinehydrochloride, mp. 227C.

Compound No.

Test item Conc. 6 l 4 l8 4 +17 lnternal carotid l6 +l6 artery blood 64+46 +16 flow I000 +39 +93 +44 4 Femoral artery l6 +62 blood flow 64 +6l+3! Heart rate l6 +2l 64 +ll l +2 1000 +l4 +18 +l3 4 2 l2 Blood pressure16 +4 l2 64 l l 3 +l 1000 +5 l2 6 +4 Test 3. Example 3.

The following compounds were obtained according to a manner similar tothat of the preceding Example 1 or 2.

No. R, R R X Physical properties (salt) l H H p-chlorophcnyl S m.p.2002()3C (HCl) 2 H H 3,4,5 trimethoxy O Amorphous form (HCl) phenyl 3 HH 2,6-dimethoxyphenyl O m.p. l99-20l.5C (HCl) 4 H H m-chlorophenyl Om.p. 244-245C (HCl) 5 H H 2-chloro-4-methoxy- O m.p. 2l5-2l9C (HCI)phenyl 6 H H 3,4-dichlorophenyl O m.p. 99C (HCl) 7 H H p-fluorophenyl Om.p. 93 95C (HCl) 8 H H m-trifluoromethyl- O m.p. 233-235C (HCI) phenyl9 H H o-chlorophcnyl S m.p. 24925lC (HCl) 10 H H p-methoxyphenyl S m.p.l6ll62C (HCl) ll H H p-fluorophenyl S m.p. l04l07C (HCl) 12 H Ho-fluorophenyl S m.p. l93-l95C (HCl) 13 H H p-hydroxyphenyl S Amorphousform (HCl) l4 H H o-hydroxypehnyl O m.p. 239-24lC (HCl) 15 H Hm-hydroxyphenyl O m.p. 252-254C (HCl) 16 H H p-hydroxyphenyl O m.p. 262C(HCl) 17 CH;, H p-hydroxyphenyl O m.p. 156C (HCl) 18 H H p-nitrophenyl Om.p. 238240C (HCl) 19 H H p-aminophenyl O m.p. 287-288C (HCl) 20 H CHp-hydroxyphenyl O m.p. 23l232C (HCl) 2l H CH 2-chloro-4-methoxy- OAmorphous form (HCl) phenyl t Example 4. silica gel in whlch ethylacetate was used as a devel- Sodium (0.13 g) was dissolved in dryethanol (30 cc), and to the ethanolic solution were addedpchlorothiophenol (0.45 g) and l-chloromethyl-6,7- dihydroxy-l,2,3,4-tetrahydroisoquinoline hydrochloride (0.7 g) in turn underice-cooling. The mixture was stirred for 1 hour at the same temperatureand for l oper. The solvent of the eluate was distilled off, and theresidue was treated with an ethanolic solution of hydrochloric acid.Precipitates were collected by filtration to give crystals (50 mg) ofl-(p-fluorophenyl)thiomethyl- 6,7-dihydroxyl,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 104 107C.

A mixture of l-chloromethyl-6,7-dihydroxy-l,2,3,4-tetrahydroisoquinoline hydrochloride (0.5 g), pfluorothiophenol (280mg), 50 percent sodium hydride (200 mg) and dry dimethylformamide (7 cc)was stirred for 1 hour at room temperature, and then for 1 hour at 50C.The reaction mixture was poured into water, and the aqueous solution wasextracted with ethyl acetate. The extract was washed with water anddried, and then the solvent was distilled off. The oily residue wassubjected to a column chromatography of hour at'room temperaturerespectively. The solvent of the solution was distilled off underreduced pressure. The residue was alkalized by ammonia, and the alkalineExample 6. solution was extracted with ethyl acetate. The ethyl ac- Thef ll i compounds were obtained according.- etate layer was washed withwater Q m The to a manner similar to that of the preceding Example ventof the ethyl acetate layer was distilled off, and the 4 or 5 residue wastreated with an ethanolic solution of hydrochloric acid. Precipitateswere collected by filtration and recrystallized from a mixed solvent ofethanol and HQ 3 ether to give crystals (100 mg) of l-(p- How -R VI)chlorophenyl)thiomethyl-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinolinehydrochloride, m.p. 200 CH XE 203C. 2 4

No. R R R, X Physical properties (salt) I H H o-chlorophenyl S m.p.24925lC (HCl) 2 H H p-methoxyphenyl S m.p. l61-l62C (HCl) 3 H Ho-fluorophenyl S m.p. l93-l95C (HCl) 4 H H p-hydroxyphenyl S Amorphousform (HCl) Example 5. Example 7.

A solution of 1-(p-hydroxyphenoxy)methyl-6,7-

dihydroxy-3,4-dihydroisoquinoline hydrobromide (120 was neutralized byaddition of hydrochloric acid, and precipitates were collected byfiltration, washed with.

water and dried to give crystals. The crystals were coverted into thecorresponding hydrochloride according i to a conventional manner to givecrystals (64 mg) of l-(p-hydroxyphenoxy)methyl-6,7-dihydroxyl ,2,3 ,4-tetrahydroisoquinoline hydrochloride, m.p. 262C.

10 percent palladium carbon (2.0 g) and cone. hydrochloric acid (3 cc)under atmospheric pressure. The reaction mixture was filtered, and thefiltrate was concentrated under reduced pressure. The concentrateExample was recrystallized from a mixed solvent of ethanol and1-(p-Benzyloxyphenoxy)rnethyl-6,7-dibenzyloxyether to give crystals(4.05 g) of l-(p- 3,4-dihydroisoquinoline hydrochloride (5.0 g) wasrehydroxyphenoxy)methyl-6,7-dihydroxy-l,2,3,4- duced by catalyticreduction in which the reaction was tetrahydrolsoquinolme hydrochloride,m.p. 262C. effected in an ethanolic solvent at 60C using per-' centpalladium carbon (1.0 g) and hydrochloric acid (2 10 cc) underatmospheric pressure. The reaction mixture Example 1 1 was filtered andthe filtrate was concentrated under re- A S n of l hlor h Ox th I 6 7duced Pressure. The concentrate was treated with a db 2 3 4t Op 9" 2?mixed solvent of methanol and ether, and thus obtained g f f l g mcrystals were recrystallized from the same mixed 501- fl r fg gg i g f s5g g f' vent to give 1 (p'hydroxyphenoxy)methyl'fi' di ess and-theconcentrate was tr t d is'ill r :1dihydroxy-l,2,3,4-tetrahydroisoquinoline hydrochloyn ea l 3 mm? Osolvent of isopropanol and ether. Preclpitates were reride, m.p. 262 C.

crystallized from the same mixed solvent to give color- Example 9. lesscrystals (0.9 g) of l-(p-chlorophenoxy)methyl-6,7- 2O dihydroxy-l 2 34-tetrahydroisoquinoline hydrochlo- The following compounds wereobtalned accordlngi rue m 2 36 to a manner similar to that of thepreceding Example 1 7 or 8.

HO 1 v Example 12. HO NH (Ix) The following compounds were obtainedaccording to a manner similar to that of the preceding Example 10 or II.

No. R R; X Physical properties (salt) I H p-chlorophenyl S m.p. ZOO-203C(HCl) 2 H 3,4.5-trimethoxy- O Amorphous form (HCl) phcnyl 3 H2,6-dimethoxyphenyl 0 m.p. |99-201.5c (HCl) 4 H m-chlorophenyl O m.p.244-245C (HCl) 5 H 2-chloro-4-methoxy- O m.pv 2l52l9C (HCl) phenyl 6 H3.4-dichlorophenyl O m.p. 99C (HCl) 7 H p-fluorophenyl O m.p. 93-95C(HCl) 8 H m-trifluoromethyl- O m.p. 233235C (HCl) phenyl 9 Ho-chlorophenyl S m.p. 24925lC (HCl) 10 H p-methoxyphenyl S m.p. l6ll62C(HCl) ll H p-fluorophenyl S m.p. l()4-l07C (HCl) 12 H 0-fluorophenyl Sm.pv l93l95C (HCl) l3 H p-hydroxyphcnyl S Amorphous form (HCl) 14 Ho-hydroxyphcnyl O m.p. 239-24lC (HCl) l5 H m hydroxyphcnyl O m.p.252254C (HCl) 16 H p-methoxyphenyl 0 mp. 24()243C (HBr) 17 (H3p-hydroxyphenyl O m.p. 156C (HCl) l8 H p-nitrophcnyl O m.p. Eli-240C(HCl) l9 H p-aminophcnyl O m.p. 287-288C (HCl) 20 H p-chlorophenyl Om.p. 227C (HCl) Example 10. l-(p-Benzyloxyphenoxy)methyl-6,7-dibenzyloxyl,2,3,4-tetrahydroisoquinoline(8.5 g) was reduced by catalytic reduction in which the reaction waseffected in 99 percent ethanolic solvent (150 cc) at C using No. RI R2 7R3 X Physical properties (salt) I H H p-chlorophcnyl S m.p. 200-203C(HCl) 2 H H 3,4,5-trimethoxy- 0 Amorphous form (HCl) phcnyl 3 Hlfi-mflhwv g ,9 m:i2.-..!2?-. .9'.-5?9 (H Continued No. R, R R XPhysical properties (salt) 4 H H m-chlorophcnyl O m.p. 244-245C (HCl) 5H H 2-chloro-4-methoxy O m.p. 2l52l9C (HCl) phenyl 6 H H3,4-dichlorophenyl O m.p. 99C (HCl) 7 H H p-fluorophenyl O m.p. 9395C(HCl) 8 H H m-trifluoromethyl- O m.p. 233-235C (HCl) phenyl 9 H Ho-chlorophenyl S m.p. 249-25lC (HCI) l0 H H p-methoxyphenyl S m.p.l6l-l62C (HCI) ll H H p-fluorophcnyl S m.p. l04-l07"C (HCI) 12 H Ho-fluorophenyl S m, I93-l95C (HCI) 13 H H p-hydroxyphenyl S Amorphousform (HCI) 14 H H o-hydroxyphenyl 0 mp 23924lC (HCI) 15 H Hm-hydroxyphenyl O m.p. 252254C (HCI) 16 H H p-methoxyphenyl 0 mp 240243C(HBr) 17 CH;, H p-hydroxyphenyl O m.p. l56C (HCI) l8 H H p-nitrophenyl Om.p. 238-240C (HCl) 19 H H p-aminophenyl O m.p. 287-288C (HCI) 20 H CH:p-hydroxyphenyl 0 mp. 231-232C (HCI) 21 H CH 2-chloro-4-methoxy- OAmorphous form (HCI) phenyl Because f the possession f the Said i i ithe 20 is intended to include nontherapeutic materials which newderivatives of l,2,3,4-tetrahydroisoquinoline of the formula [I] andpharmaceutically acceptable salts thereof are useful as a relaxant onsmooth muscles and especially on vascular-smooth and visceral smoothmuscles.

The new derivatives of l,2,3,4- tetrahydroisoquinoline of the formula[I] and pharmaceutically acceptable salts thereof can be administered bythe conventional methods the conventional types of unit dosages or withthe conventional pharmaceutical carriers to produce relaxing activitieson smooth muscles of domestic animals.

Thus, they can be used in the form of pharmaceutical preparations, inadmixture with a pharmaceutical organic or inorganic carrier materialsuitable for enteral or parenteral applications. Oral administration bythe use of tablets, capsules or in liquid form such as suspension,solutions or emulsions is particularly advantageous. When formed intotablets, the conventional binding and disintegrating agents used intherapeutic unit dosages can be employed. Illustrative of binding agentsthere can be mentioned glucose, lactose, gum acacia, gelatin, mannitol,starch paste, magnesium trisilicate and talc. lllustrative ofdisintigrating agents there can be mentioned corn starch, keratin,colloidal silica and potato starch. When administered as liquids theconventional liquid carriers can be used.

The unit dosage or therapeutically effective quantity of the compounds[I] and pharmaceutically acceptable salts thereof for human beings canvary over wide limits such as that of 0.01 milligram to about 100milligrams. The upper limit is limited only by the degree of effectdesired and economical considerations. For oral administration it ispreferable to employ from about 1 milligram to about 100 milligrams ofthe therapeutic agent per unit dosage. It is indicated from animalexperiments that about 0.1 to about 10 milligrams dosages administeredorally three times daily as needed will provide a preferred dailydosage. Of course, the dosage of the particular therapeutic agent usedcan vary considerably, such as the age of the patient and the degree oftherapeutic effect desired. Each unit dosage form of the noveltherapeutic compounds can contain from about 0.5 to about 99.5 percentof the novel therapeutic agents by weight of the entire composition withthe remainder comprising conventional pharmaceutical carriers. By theterm pharmaceutical carrier it are conventionally used with unit dosageand include fillers, diluents, binders, lubricants, disintegratingagents and solvents. Of course, it is possible to administer the noveltherapeutics, i.e. the pure compounds, without the use of apharmaceutical carrier. It is also possible to administer the newderivatives of l,2,3,4- tetrahydroisoquinoline of the formula [I] andpharmaceutically acceptable salts thereof in the form of a mixture withother agents which are used as a relaxant on smooth muscles andespecially on vascular-smooth and visceral-smooth muscles.

Formulae of the tablets are given below. I

Ingredient (mg) g) l-( p-chlorophenoxy)methyl- 6,7-dihydroxy-l,2,3,4-l.() tetrahydroisoquinoline I hydrochloride Dextrin Potato starchLactose Spray-dry lactose Avicel (Trademark) Methyl cellulose Magnesiumstearate Potassium carboxymethyl cellulose Colloidal silicic acid TotalCoated to make l Formula of an injectable solution is given below.

Ingredient g) l:(p-Chlorophenoxy)methyl-6,7- dihydroxy-l,2,3,4-tetrahydrol isoquinoline hydrochloride Sodium chloride Distilledwater for injection 9.0 to make 5 cc wherein R, and R are each ahydrogen or lower alkyl having 1 to 2 carbon atoms, X is an oxygen orsulfur atom, and R is phenyl having substituted thereon a substituentselected from the group consisting of lower alkoxy, hydroxy, amino,nitro, trifluoromethyl, trichloromethyl, tribomomethyl and halogen, oris phenyl having thereon two identical halogen substituents, a halogenand a lower alkyl substituent, or two lower alkoxy substituents, or isphenyl having thereon three lower alkoxy substituents, andpharmaceutically acceptable salts thereof, wherein lower refers to l to6 carbon atoms.

2. A compound of claim 1, wherein R,, R and X are each as defined above,and R is phenyl having a substituent selected from a group consisting ofa lower alk-' oxy, hydroxy, amino, nitro, trifluoromethyl,trichloromethyl, tribromomethyl and halogen.

3. The compound of claim 1, wherein R,, R and X are each as definedabove, and R is phenyl having 2 substituents selected from a groupconsisting of lower alkoxy, hydroxy, amino, nitro, halo (lower) alkyland halogen.

4. A compound of claim 2, wherein R,, R and X are each as defined above,and R is phenyl having a halogen atom substituent.

5. A compound of claim 4, wherein R, and R are both hydrogen atoms, X isas defined above, and R is a phenyl having a chlorine substituent.

6. A compound of claim 5, wherein R, and R are both hydrogen atoms, X isas defined above, and R is p-chlorophenyl.

7. The compound of claim 4, wherein R, and R are both hydrogen atoms, Xis oxygen and R is pchlorophenyl.

8. The compound according to claim 5, wherein R, and R are both hydrogenatoms, X is sulfur, and R is p-chlorophenyl.

9. The compound of claim 5, wherein R, and R are both hydrogen atoms, Xis oxygen, and R is mchlorophenyl.

10. The compound of claim 5, wherein R, and R are both hydrogen atoms, Xis sulfur, and R is ochlorophenyl.

11. A compounds claim 4, whererin R, and R are both hydrogen, X isoxygen or sulfur, and R, is phenyl having a fluorine substituent.

12. The compound of claim 11, wherein R, and R are both hydrogen atoms,X is oxygen, and R is pfluorophenyl.

13. A compound of claim 11, wherein R, and R are both hydrogen, X is asulfur, and R .is o-fluorophenyl.

14. The compound of claim 11, wherein R, and R are both hydrogen, X issulfur, and R, is pfluorophenyl.

15. A compound of claim 2, wherein R, and R are each hydrogen or a loweralkyl of l to 2 carbon atoms X is oxygen or sulfur, and R is phenylhaving an hydroxy substituent.

16. The compound of claim 15, wherein R, and R are both hydrogen, X isoxygen, and R, is ohydroxyphenyl.

17. The compound of claim 15, wherein R, and R, are both hydrogen, X isan oxygen, and R, is mhydroxyphenyl.

18. The compound of claim 15, wherein R, and R, are both hydrogen, X isoxygen, and R is phydroxyphenyl.

19. The compound of claim 15, wherein R, and R are both hydrogen, X issulfur, and R is phydroxyphenyl.

20. The compound of claim 15, wherein R, is methyl, R is hydrogen, X isoxygen and R is p-hydroxyphenyl.

21. The compound of claim 15, wherein R, is hydrogen, R is methyl, X isoxygen and R is phydroxyphenyl.

22. The compound of claim 2, wherein R, and R are both hydrogen, X isoxygen or sulfur atom, and R, is phenyl having a lower alkoxysubstituent.

23. The compound of claim 22, wherein R, and R are both hydrogen, X isoxygen, and R is pmethoxyphenyl.

24. The compound of claim 22, wherein R, and R are both hydrogen, X issulfur, and R is pmethoxyphenyl.

25. The compound of claim 2, wherein R, and R are both hydrogen, X isoxygen, and R is phenyl having a halo (lower) alkyl, substituent.

26. The compound of claim 25, wherein R, and R are hydrogen, X isoxygen, and R is trifluoromethylphenyl.

27. The compound of claim 2, wherein R, and R are both hydrogen, X isoxygen, and R is p-nitrophenyl.

28. The compound of claim 2, wherein R, and R are both hydrogen, X isoxygen, and R, is p-aminophenyl.

29. The compound of claim 3, wherein R, and R are each hydrogen or loweralkyl of l-2 carbon atoms, X is oxygen, and R is phenyl having 2substituents selected from a group consisting of a lower alkoxy andhalogen.

30. The compound of claim 29, wherein R, and R, are both hydrogen, X isoxygen, and R is phenyl having 2 lower alkoxy substituents.

31. The compound of claim 30, wherein R, and R are both hydrogen X isoxygen, and R is 2,6- dimethoxyphenyl.

32. The compound of claim 29, wherein R, and R are each hydrogen orlower alkyl having 1 to 2 carbon atoms, X is oxygen, and R is phenylhaving lower alkoxy substituent and a halogen substituent.

33. The compound of claim 32, wherein R, and R are hydrogen, X isoxygen, and R is 2-chloro-4- methoxyphenyl.

34. The compound of claim 32, wherein R, is hydrogen, R, is methyl, X isoxygen, and R is 2-chloro-4- methoxyphenyl.

35. The compound of claim 29, wherein R, and R are both hydrogen, X isoxygen, and R is phenyl having 2 halogen atom substituents.

36. The compound of claim 35, wherein R, and R are both hydrogen, X isoxygen, and R, is 3,4- dichlorophenyl.

37. The compound of claim 1, wherein R, and R are both hydrogen, X isoxygen, and R, is phenyl having 3 lower alkoxy substituents.

38. The compound of claim 37, wherein R, and R are both hydrogen, X isoxygen, and R is phenyl having three methoxy substituents.

39. The compound of claim 38, wherein R, and R are both hydrogen, X isoxygen, and R is 3,4,5-

trimethoxyphenyl.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFIQATE OF ORRECTIONPATENT No. 3,846,432

DATED November 5, 1974 P v R s KUNIHIKO TANAKA ET AL age 1 of 2 it iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

, Column 4, iine 31, after "out" insert --in--; iine 40, after "out"insert --in--; iine 44, after "out" insert --in--; iine 45, after"soivent" insert --such--; line 54, deiete 'with" and insert --the--;i-ine 55, deiete "connected and insert --converted--.

Coiumn 5, iine 47, deiete "connected" and insert --c0nverted--.

Column Coiumn Coiumn Coiumn Coiumn --i-(p-Hydroxyphenyi 9, in the table,under Coiumn "R No. 14, deiete "o-hydroxypehnyi and insert--o-hydroxyphen yi i0, iine 67, deiete cov-" and insert --conv- 13, line44, deiete "disintigrating" and insert --disintegrating--.

i5, iine 6, in Ciaim 1 deiete "tribomomethyi and insert --tribromomethyiUNITED STATES PATENT AND TRADEMARK OFFICE QTIFICATE 0F c CQRRECTIGNPATENT NO. ;3,84 6.-,432 DATED November 5, i974 Page 2 of 2 INVENTOR(S)KUNIHIKO TANAKA ET AL It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below: 9

Column 15, Claim ll, line 44, delete "compounds" and insert ---compoundof--.

Q Column 15, Claim 15, line 57, after "atoms" insert a comma Signed andScale this 9 twenty-second Day Of June1976 [SEAL] Arrest:

RUTH c. MASON c. MARSHALL DANN 4! 19811718 fficer Commissioner ofParents and Trademarks

2. A compound of claim 1, wherein R1, R2 and X are each as definedabove, and R3 is phenyl having a substituent selected from a groupconsisting of a lower alkoxy, hydroxy, amino, nitro, trifluoromethyl,trichloromethyl, tribromomethyl and halogen.
 3. The compound of claim 1,wherein R1, R2 and X are each as defined above, and R3 is phenyl having2 substituents selected from a group consisting of lower alkoxy,hydroxy, amino, nitro, halo (lower) alkyl and halogen.
 4. A compound ofclaim 2, wherein R1, R2 and X are each as defined above, and R3 isphenyl having a halogen atom substituent.
 5. A compound of claim 4,wHerein R1 and R2 are both hydrogen atoms, X is as defined above, and R3is a phenyl having a chlorine substituent.
 6. A compound of claim 5,wherein R1 and R2 are both hydrogen atoms, X is as defined above, and R3is p-chlorophenyl.
 7. The compound of claim 4, wherein R1 and R2 areboth hydrogen atoms, X is oxygen and R3 is p-chlorophenyl.
 8. Thecompound according to claim 5, wherein R1 and R2 are both hydrogenatoms, X is sulfur, and R3 is p-chlorophenyl.
 9. The compound of claim5, wherein R1 and R2 are both hydrogen atoms, X is oxygen, and R3 ism-chlorophenyl.
 10. The compound of claim 5, wherein R1 and R2 are bothhydrogen atoms, X is sulfur, and R3 is o-chlorophenyl.
 11. A compoundsclaim 4, whererin R1 and R2 are both hydrogen, X is oxygen or sulfur,and R3 is phenyl having a fluorine substituent.
 12. The compound ofclaim 11, wherein R1 and R2 are both hydrogen atoms, X is oxygen, and R3is p-fluorophenyl.
 13. A compound of claim 11, wherein R1 and R2 areboth hydrogen, X is a sulfur, and R3 is o-fluorophenyl.
 14. The compoundof claim 11, wherein R1 and R2 are both hydrogen, X is sulfur, and R3 isp-fluorophenyl.
 15. A compound of claim 2, wherein R1 and R2 are eachhydrogen or a lower alkyl of 1 to 2 carbon atoms X is oxygen or sulfur,and R3 is phenyl having an hydroxy substituent.
 16. The compound ofclaim 15, wherein R1 and R2 are both hydrogen, X is oxygen, and R3 iso-hydroxyphenyl.
 17. The compound of claim 15, wherein R1 and R2 areboth hydrogen, X is an oxygen, and R3 is m-hydroxyphenyl.
 18. Thecompound of claim 15, wherein R1 and R2 are both hydrogen, X is oxygen,and R3 is p-hydroxyphenyl.
 19. The compound of claim 15, wherein R1 andR2 are both hydrogen, X is sulfur, and R3 is p-hydroxyphenyl.
 20. Thecompound of claim 15, wherein R1 is methyl, R2 is hydrogen, X is oxygenand R3 is p-hydroxyphenyl.
 21. The compound of claim 15, wherein R1 ishydrogen, R2 is methyl, X is oxygen and R3 is p-hydroxyphenyl.
 22. Thecompound of claim 2, wherein R1 and R2 are both hydrogen, X is oxygen orsulfur atom, and R3 is phenyl having a lower alkoxy substituent.
 23. Thecompound of claim 22, wherein R1 and R2 are both hydrogen, X is oxygen,and R3 is p-methoxyphenyl.
 24. The compound of claim 22, wherein R1 andR2 are both hydrogen, X is sulfur, and R3 is p-methoxyphenyl.
 25. Thecompound of claim 2, wherein R1 and R2 are both hydrogen, X is oxygen,and R3 is phenyl having a halo (lower) alkyl, substituent.
 26. Thecompound of claim 25, wherein R1 and R2 are hydrogen, X is oxygen, andR3 is trifluoromethylphenyl.
 27. The compound of claim 2, wherein R1 andR2 are both hydrogen, X is oxygen, and R3 is p-nitrophenyl.
 28. Thecompound of claim 2, wherein R1 and R2 are both hydrogen, X is oxygen,and R3 is p-aminophenyl.
 29. The compound of claim 3, wherein R1 and R2are each hydrogen or lower alkyl of 1-2 carbon atoms, X is oxygen, andR3 is phenyl having 2 substituents selected from a group consisting of alower alkoxy and halogen.
 30. The compound of claim 29, wherein R1 andR2 are both hydrogen, X is oxygen, and R3 is phenyl having 2 loweralkoxy substituents.
 31. The compound of claim 30, wherein R1 and R2 areboth hydrogen X is oxygen, and R3 is 2,6-dimethoxyphenyl.
 32. Thecompound of claim 29, wherein R1 and R2 are each hydrogen or lower alkylhaving 1 to 2 carbon atoms, X is oxygen, and R3 is phenyl having loweralkoxy substituent and a halogen substituent.
 33. The compound of claim32, wherein R1 and R2 are hydrogen, X is oxygen, and R3 is2-chloro-4-methoxyphenyl.
 34. The compound of claim 32, wherein R1 ishydrogen, R2 is methyl, X is oxygen, and R3 is 2-chloro-4-methoxyphenyl.35. The compound of claim 29, wherein R1 and R2 are both hydrogen, X isoxygen, and R3 is phenyl having 2 halogen atom substituents.
 36. Thecompound of claim 35, wherein R1 and R2 are both hydrogen, X is oxygen,and R3 is 3,4-dichlorophenyl.
 37. The compound of claim 1, wherein R1and R2 are both hydrogen, X is oxygen, and R3 is phenyl having 3 loweralkoxy substituents.
 38. The compound of claim 37, wherein R1 and R2 areboth hydrogen, X is oxygen, and R3 is phenyl having three methoxysubstituents.
 39. The compound of claim 38, wherein R1 and R2 are bothhydrogen, X is oxygen, and R3 is 3,4,5-trimethoxyphenyl.